Regulatory affairs-Introduction to CTD

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Drug Regulatory Affairs

By, Mahesh Shinde

The Bridge BetweenPharma Companies & Govt.

Agency

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Regulatory affairs

• It is by no means boring! It’s interesting.

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Role of Regulatory Affairs

What is this?

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Regulatory System

YES YES YES

YES

YES

YES

Govt. Prescriber Distributor Patient

Govt.

Prescriber

Distributor

Patient

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• Drug = medicinal product

= pharmaceutical product

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Drug regulatory affairsAny activity with drugs

By whom? (the authority)

no (=does not belong to drug regulatory affairs)

yes

Prior authorisation needed?

Based on which (objective and subjective) criteria?

Subject to regular control (quality, inspection)?

By whom? (the authority)Based on which (objective and subjective) criteria?

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Activities with drugs…

• research (chemical, biological)• clinical trials on human beings• manufacture• registration – evaluation– authorisation

• (wholesale) distribution

continued

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Activities with drugs (cont’d)

• pricing• prescribing• reimbursement/subsidy• advertising (if any)• special control (e.g. narcotics)• post-marketing surveillance– national drug quality control lab– adverse effect reporting system

• (retail) distribution• etc.

poppy

Quality = Quality of Personnel (Qualification, Training…)

+ Quality of Materials (Specifications, Approved Suppliers...)

+ Quality of Means (Qualified equipment's, maintenance…)

+ Quality of Media (GMP premises, Controlled environment…)

+ Quality of Methods (Calibration, Validation…)

Composition of Quality

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QUALITYQUALITY

Raw Materials

Personnel

Procedures

Validated processes

EquipmentPremises

Environment

Packing Materials

Functions of a Quality UnitFunctions of a Quality Unit

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Quality Control

– Sampling and testing of components Raw materials,

Packing materials, intermediates and finished

products

– Compliance to Good Laboratory Practices (GLPs)

Functions of a Quality UnitFunctions of a Quality Unit

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Quality Assurance

– Designing robust quality systems

– Ensure compliance to relevant

regulatory requirements

– Ensure compliance to

requirements of Good

Manufacturing Practices (GMP)

Value addition in QA functionValue addition in QA function

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Quality Assurance:

– Perform structured self-inspection

audits at regular intervals to prevent

any failure or non-conformance

– Critically analyze the quality non-

conformance issues and suggest

corrective and preventive actions

Value addition in QA function

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Quality Assurance:

– Perform documentation audit to

ensure realistic recording of all the

relevant process parameters

– Review the adequacy of in-process

control checks to prevent any

potential failures

Value addition in QA function

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Quality Assurance:– Training & Knowledge Management

– Perform literature survey of FDA /

ICH / ISO guidelines, revisions in the

Pharmacopoeial specifications and the

current regulatory requirements and

provide training to the production

personnel.

What is Dossier?

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• Dossier is collection or file of documents that contains all the technical data of pharmaceutical product to be approved/ registered /marketed in country.

• It is commonly called as registration dossier.

In US : New Drug ApplicationIn EU : Marketing Authorization Application

What is DMF?Drug Master File (DMF)

• US : United State Drug Master File (US-DMF)• EU : European Drug Master File (EDMF) or

Active Substance Master File (ASMF)

• TYPES OF DMFs• The types of DMFs are:• Type I - Manufacturing Site, Facilities, Operating Procedures, and Personnel (no

longer applicable)• Type II - Drug Substance, Drug Substance Intermediate, and Material Used in

Their Preparation, or Drug Product• Type III - Packaging Material• Type IV - Excipient, Colorant, Flavor, Essence, or Material Used in Their

Preparation• Type V - FDA Accepted Reference Information

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What is CTD/eCTD?Common Technical Documents (CTD)

• The Common Technical Document (CTD) is a set of specification for application dossier for the registration of Medicines and designed to be used across Europe, United States & ROW.

• Its electronic version called as Electronic Common Technical Document (eCTD)

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The CTD Triangle

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Module 1 Administrative & Prescribing Information (Region Specific):

Should Contain Documents specific to each region:

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Module 1 Administrative & Prescribing Information (Region Specific):

(1) SITE MASTER PLAN OF PLANT

(2) COMPANY PROFILE IN SHORT

(3) ATTESTED COPY OF MANUFACTURING LICENCE

(4) ATTESTED COPY OF PRODUCT PERMISSION FROM FDA

(5) ATTESTED COPY OF COPP

(6) ATTESTED COPY OF WHO/GMP CERTIFICATE

(7) COA OF SAMPLE

(8) ATTESTED COPY OF WHOLE SELL LICENCE.

(9) LETTER OF AUTHORISATION

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Module 2 CTD Summaries (QOS):

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It contain 7 sections in the following order:

2.1 CTD Table of content (Module 2-5)2.1 CTD Table of content (Module 2-5)

2.2 CTD Introduction2.2 CTD Introduction

2.3 Quality Overall Summary 2.3 Quality Overall Summary

2.4 Non-Clinical Overview 2.4 Non-Clinical Overview

2.5 Clinical Overview2.5 Clinical Overview

2.6 Non-Clinical Summary2.6 Non-Clinical Summary

2.7 Clinical Summary2.7 Clinical Summary

Module 3 Quality: Chemistry, Manufacturing & Controls (CMC)

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3.1 Table of content (Module 3)3.1 Table of content (Module 3)

3.2 Body of Data3.2 Body of Data

3.2 S Drug Substance 3.2 S Drug Substance

3.2 S1 General Information (Name, Mfg.) 3.2 S1 General Information (Name, Mfg.)

3.2 S2 Manufacture3.2 S2 Manufacture

3.2 S3 Characterization 3.2 S3 Characterization

3.2 S4 Control of Drug Substance (Specification, Analytical procedures, Validation of Analytical procedures, etc. )

3.2 S4 Control of Drug Substance (Specification, Analytical procedures, Validation of Analytical procedures, etc. )

3.2 S5 Reference Standards3.2 S5 Reference Standards

3.2 S6 Stabil ity 3.2 S6 Stabil i ty


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3.2 P Drug Product 3.2 P Drug Product

3.2 P1 Description and Composition of the Drug Product3.2 P1 Description and Composition of the Drug Product

3.2 P2 Pharmaceutical Development (name, dosage form)3.2 P2 Pharmaceutical Development (name, dosage form)

3.2 P3 Manufacturer3.2 P3 Manufacturer

3.2 P4 Control of Excipients3.2 P4 Control of Excipients

3.2 P5 Control of Drug Product (Specification, Analytical procedures, Validation of Analytical procedures, etc. )

3.2 P5 Control of Drug Product (Specification, Analytical procedures, Validation of Analytical procedures, etc. )

3.2 P6 Reference Standards3.2 P6 Reference Standards

3.2 P7 Stability 3.2 P7 Stability


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3.2 A Appendices3.2 A Appendices

3.2 A1 Facility & Equipment's3.2 A1 Facility & Equipment's

3.2 A2 Advertising agents safety evaluation3.2 A2 Advertising agents safety evaluation

3.2 A3 Excipients3.2 A3 Excipients

3.2 R Regional Information3.2 R Regional Information

3.3 Literature References3.3 Literature References

Module 4 Non-Clinical Study Reports:

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4.2 Study Reports4.2 Study Reports

4.2.1 Pharmacology4.2.1 Pharmacology

4.2.1. 1. Pharmacodynamics 4.2.1. 1. Pharmacodynamics

4.2.1. 2. Safety Pharmacology 4.2.1. 2. Safety Pharmacology

4.2.1. 3. Pharmacodynamics Drug Interaction 4.2.1. 3. Pharmacodynamics Drug Interaction

4.2.2 Pharmacokinetics4.2.2 Pharmacokinetics

4.2.2. 1. ADME 4.2.2. 1. ADME

4.2.2. 2. Pharmacokinetic Drug Interaction 4.2.2. 2. Pharmacokinetic Drug Interaction

4.2.2. 3. Other Pharmacokinetic Study 4.2.2. 3. Other Pharmacokinetic Study

Module 4 Non-Clinical Study Reports:

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4.2.3 Toxicology4.2.3 Toxicology

4.2.3. 1. Single/Repeat Dose Toxicity 4.2.3. 1. Single/Repeat Dose Toxicity

4.2.3. 2. Genotoxicity 4.2.3. 2. Genotoxicity

4.2.3. 3. In-Vivo/Vitro Toxicity 4.2.3. 3. In-Vivo/Vitro Toxicity

4.2.3. 4. Carcinogenicity 4.2.3. 4. Carcinogenicity

4.2.3. 5. Local Tolerance/Dependence 4.2.3. 5. Local Tolerance/Dependence

4.2.3. 6. Other Studies 4.2.3. 6. Other Studies


Module 5 Clinical Study Reports:

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5.2 Tabular listing of Clinical Studies 5.2 Tabular listing of Clinical Studies

5.3 Clinical study reports 5.3 Clinical study reports

5.3.1 Reports of Biopharmaceutical (BA-BE) Study 5.3.1 Reports of Biopharmaceutical (BA-BE) Study

5.3.2 Reports of Pharmacokinetic (biomaterial) study 5.3.2 Reports of Pharmacokinetic (biomaterial) study

5.3.3 Reports of Pharmacokinetic (PK) studies 5.3.3 Reports of Pharmacokinetic (PK) studies

5.3.4 Reports of Pharmacodynamics (PD) studies 5.3.4 Reports of Pharmacodynamics (PD) studies

5.3.4 Reports of Efficacy and Safety studies 5.3.4 Reports of Efficacy and Safety studies

5.3.4 Reports of Post-Marketing experience 5.3.4 Reports of Post-Marketing experience

5.3.4 Case Report Forms & Individual patient listings5.3.4 Case Report Forms & Individual patient listings


Sample

• Dossier • DMF

Regulatory Compliance

National Regional Global

Regulatory Compliance

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National (India)

License Application Receipt

Manufacturing license Form No. 24 Form No. 25

Test license Form No. 30 Form No. 29

Import license Form No. 12 Form No.11

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Compliance to (Drugs & Cosmetics Act 1940 & Rules under)

National (India)

Drug Regulatory approval

Schedule Y ComplianceForm 44

Manufacturing Schedule M Compliance

Documentation Schedule U Compliance

Packaging Schedule P Compliance

API/Excipients/FP/PM IP Inputs if not BP/USP/ or IH

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Regulatory Dossier Regulatory approach:

Parameters US Europe Other markets India

API USP Ph.Eur. USP / Ph.Eur. IP

USDMF COS (CEP) / EDMF DMF requirement depends on the target market

Excipients USP Ph.Eur. USP / Ph.Eur. IP

Reference product US Europe Depends on the target market

Indian (if not available, then US or Europe)

Packaging materials

Complying to USP Ph.Eur. USP / Ph.Eur. IP

Finished product USP As per Ph.Eur. General requirement

USP / Ph.Eur. IP

Submission batch 1 2 2 or 3 -

Submission batch size

100,000 units or 1/10th of commercial

batch

100,000 units or 1/10th of

commercial batch

Depends on the target market

No such requirement

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Regulatory Dossier Regulatory approach:

Parameters US Europe Other markets India

Stability data 1 batch 2 batches 2 or 3 batches 3 batches

Stability condition Zone I & II condition Zone I & II condition Depends on the target market

Zone IV condition

Comparative dissolution study

3 media 3 media Depends on the target market

1 to 3 media

Input materials TSE/BSE, OVI statements

TSE/BSE Depends on the target market

No such requirement

Packaging materials Food grade certificate Food grade certificate Depends on the target market

No such requirement

Method validation data As per ICH ICH ICH No such guideline

Process validation data

Not required Not required Depends on the target market

Not required for submission

Bioequivalence study US reference product under fast and fed

condition

European reference product (generally

under fasting condition)

Generally fasting bio study

Fasting bio study

Bioequivalence study In USFDA approved CRO anywhere in the

world

MHRA/EU approved CRO anywhere

Depends on the target market

Indian study required

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Regulatory Authorities

India: DCGI & State Drug Administration European Union: MHRA USA : Food and Drug Administration (FDA) Australia : Therapeutic Goods Administration Newzeland : Medsafe South Africa: Medicines council control Japan : Ministry of Health & Labour Welfare Switzerland : Swissmedic Brazil : ANVISA (The National Health Surveillance Agency)

Mexico: COFEPRIS (The Federal Commission for the Protection against Sanitary Risk)

Chile : ISP - Instituto de Salud Pública de Chile Columbia: INVIMA – Instituto Nacional de Vigilancia de Medicamentos Alimentos Carrera 68 D No. 17 - 11 / 21 Argentina: ANMAT - set in 1992 Argentine National Administration of Drugs, Food & Medical TechnologyFrance: Agence Française de Sécurité Sanitaire des Produits de SantéGermany: Federal Institute for Drugs and Medical Devices

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Important sitesRegulatory sites:

www.fda.govwww.tga.gov.au http://www.emea.europa.eu/ www.ministeriodesalud.go.cr www.mspas.gob.gthttp://www.minsa.gob.pa/minsa2006/inicio.phphttp://www.minsa.gob.nihttp://www.salud.gob.hn/www.cssp.gob.svhttp://www.sns.gov.bo/http://www.inh.gov.ec/http://www.mspbs.gov.py/http://www.msp.gub.uy/index_1.htmlhttp://digemid.minsa.gob.pehttp://www.inhrr.gov.vehttp://pharmacos.eudra.org

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Important sites

Useful links:

•www.usp.org •www.pheur.org •www.jpdb.nihs.go.jp •www.picscheme.org •www.pda.org •www.phrma.org •www.pharmacy.org •www.elsevier.com •www.ich.org•www.ijpsonline.com •www.pharmj.com •www.scripnews.com

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E-mail: [email protected]

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Regulatory affairs-Introduction to CTD

Healthcare

Transcript of Regulatory affairs-Introduction to CTD